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Programming of PMN host-defense function during transendothelial migration

Award Number: R01HL045638
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/11/1993
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Programming of PMN host-defense function during transendothelial migration - PROJECT SUMMARY / ABSTRACT Polymorphonuclear neutrophil (PMN or neutrophil) maintain human health by rapidly eliminating the invading pathogens. These circulating cells transmigrate across the endothelial adherens junctions (AJs) to enter into the infected tissue and to clear the pathogens. Little is known about the role of mechanical forces which PMN experience during transmigration across the endothelium. Our Supporting Data describe the potentially important role of adherens junctions in activating PMN’s host defense function. We observed that activation of PMN-expressed Piezo1 during paracellular transmutation induced calcium influx, which in turn, promptly stabilized Hif1α and upregulated expression of NADPH oxidase 4 (Nox4) in PMN to program these cells to efficient “killers” of the pathogens. These findings have for the first time linked PMN-expressed Piezo1 to the host-defense function, leading to the fundamental question “how Ca2+ influx in PMN via Piezo1 program the host-defense function of PMN?” In Aim 1, we will determine the role of PMN-expressed Piezo1 signaling pathway in activating the host-defense function of transmigrating PMN. Here we will delineate the signaling pathways downstream of Piezo1 activation that promptly stabilizes Hif1α in PMN and programs PMN to become more efficient bacterial “killers”. The studies will involve genetic analysis of Piezo1- Hif1α signaling of the transmigrating PMN such as PMN-specific Piezo1 and Hif1α knockout mice. We will also determine whether pharmacological activation of Piezo1 or expression of gain-of-function Piezo1 mutant in PMN is sufficient to activate the PNM defense system in the relevant P. aeruginosa-induced pneumonia model. In Aim 2, we will determine the role of PMN-expressed Nox4 in regulating oxidative and lytic properties of PMN and in the efficient elimination of pathogens in lung. These studies will address the function of Nox4 in PMN in the mechanism of innate immune defense program. Using in vitro and in vivo experiments, we will determine how Hif1α induces activation of Nox4 gene and how Nox4 regulates oxidative and lytic properties of phagolysosome and efficient pathogen killing. The proposed studies will be essential for understanding the regulation of PMN host-defense function with the goal of identifying therapeutic potential of Piezo1 activators.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $719,502 )
2025	2025	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	002	37	7/18/2025	NON-COMPETING CONTINUATION	$719,502
2025	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	36	12/21/2024	NON-COMPETING CONTINUATION	$0
2025	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	001	36	6/5/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $719,502

Issue Date FY: 2024 ( Subtotal = $779,158 )
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	003	36	7/27/2024	NON-COMPETING CONTINUATION	$705,113
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	002	35	6/27/2024	SUPPLEMENT FOR EXPANSION	$11,097
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	004	36	7/30/2024	SUPPLEMENT FOR EXPANSION	$62,948
2024	2022	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	001	34	5/2/2024	COMPETING CONTINUATION	$175,365
2024	2021	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	33	5/2/2024	NON-COMPETING CONTINUATION	-$175,365
														Subtotal = $779,158

Issue Date FY: 2023 ( Subtotal = $719,502 )
2023	2023	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	35	7/12/2023	NON-COMPETING CONTINUATION	$719,502
														Subtotal = $719,502

Issue Date FY: 2022 ( Subtotal = $719,502 )
2022	2022	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	001	34	7/15/2022	COMPETING CONTINUATION	$719,502
2022	2021	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	33	7/14/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $719,502

Issue Date FY: 2021 ( Subtotal = $711,033 )
2021	2021	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	33	3/15/2021	NON-COMPETING CONTINUATION	$711,033
														Subtotal = $711,033

Issue Date FY: 2020 ( Subtotal = $695,574 )
2020	2020	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	001	32	6/22/2020	SUPPLEMENT FOR EXPANSION	$52,776
2020	2020	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	32	3/18/2020	NON-COMPETING CONTINUATION	$642,798
														Subtotal = $695,574

Issue Date FY: 2019 ( Subtotal = $642,798 )
2019	2019	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	31	4/29/2019	NON-COMPETING CONTINUATION	$642,798
														Subtotal = $642,798

Issue Date FY: 2018 ( Subtotal = $642,798 )
2018	2018	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	001	30	4/13/2018	COMPETING CONTINUATION	$642,798
2018	2018	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	003	30	7/2/2018	COMPETING CONTINUATION	$163,705
2018	2017	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	002	29	7/2/2018	NON-COMPETING CONTINUATION	-$163,705
2018	2017	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	29	4/12/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $642,798

Issue Date FY: 2017 ( Subtotal = $319,000 )
2017	2017	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	29	3/27/2017	NON-COMPETING CONTINUATION	$319,000
2017	2012	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	001	24	5/8/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $319,000

Issue Date FY: 2016 ( Subtotal = $319,000 )
2016	2016	UNIVERSITY OF ILLINOIS AT CHICAGO	890 SOUTH MARSHFIELD AVENUE	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	28	2/25/2016	NON-COMPETING CONTINUATION	$319,000
														Subtotal = $319,000

Issue Date FY: 2015 ( Subtotal = $314,215 )
2015	2015	UNIVERSITY OF ILLINOIS AT CHICAGO	890 SOUTH MARSHFIELD AVENUE	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	27	3/2/2015	NON-COMPETING CONTINUATION	$314,215
														Subtotal = $314,215

Issue Date FY: 2014 ( Subtotal = $319,000 )
2014	2014	UNIVERSITY OF ILLINOIS AT CHICAGO	890 SOUTH MARSHFIELD AVENUE	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	001	26	3/18/2014	COMPETING CONTINUATION	$319,000
2014	2012	UNIVERSITY OF ILLINOIS AT CHICAGO	890 SOUTH MARSHFIELD AVENUE	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	24	3/13/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $319,000

Issue Date FY: 2012 ( Subtotal = $450,483 )
2012	2012	UNIVERSITY OF ILLINOIS AT CHICAGO	890 SOUTH MARSHFIELD AVENUE	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	24	6/12/2012	NON-COMPETING CONTINUATION	$450,483
														Subtotal = $450,483

Issue Date FY: 2011 ( Subtotal = $455,033 )
2011	2011	UNIVERSITY OF ILLINOIS AT CHICAGO	890 SOUTH MARSHFIELD AVENUE	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	23	6/3/2011	NON-COMPETING CONTINUATION	$455,033
														Subtotal = $455,033

Issue Date FY: 2010 ( Subtotal = $449,797 )
2010	2010	UNIVERSITY OF ILLINOIS AT CHICAGO	890 SOUTH MARSHFIELD AVENUE	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	22	5/28/2010	NON-COMPETING CONTINUATION	$392,500
2010	2010	UNIVERSITY OF ILLINOIS AT CHICAGO	890 SOUTH MARSHFIELD AVENUE	CHICAGO	IL	60612	COOK	USA	Cardiovascular Diseases Research	001	22	6/23/2010	SUPPLEMENT FOR EXPANSION	$57,297
														Subtotal = $449,797

Issue Date FY: 2009 ( Subtotal = $392,500 )
2009	2009	UNIVERSITY OF ILLINOIS AT CHICAGO	890 SOUTH MARSHFIELD AVENUE	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	21	5/12/2009	NON-COMPETING CONTINUATION	$392,500
														Subtotal = $392,500

Issue Date FY: 2008 ( Subtotal = $392,500 )
2008	2008	UNIVERSITY OF ILLINOIS AT CHICAGO	890 SOUTH MARSHFIELD AVENUE	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	20	7/21/2008	COMPETING CONTINUATION	$392,500
														Subtotal = $392,500

Issue Date FY: 2007 ( Subtotal = $369,482 )
2007	2007	UNIVERSITY OF ILLINOIS AT CHICAGO	809 S MARSHFIELD AVE, 511 MB	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	19	5/24/2007	NON-COMPETING CONTINUATION	$369,482
														Subtotal = $369,482

Grand Total All Awards = $12,595,776

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Programming of PMN host-defense function during transendothelial migration

Award Number: R01HL045638

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/11/1993

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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